A novel off-the-shelf chimeric antigen receptor natural killer cell (CAR-NK) product called FT596 may prove to be an active therapy for B-cell malignancies. This agent is designed to overcome several challenges inherent in CAR T-cell therapy, including CD19-antigen escape, which leads to relapse in patients who initially respond to CAR T-cell therapy.
In preclinical studies, FT596 was as effective as existing CAR T-cell platforms in killing cancer cells in vivo, and the combination of FT596 plus rituximab killed lymphoma cancer cells that were no longer responding to CAR T-cell therapy due to the loss of the CD19 antigen target.1
FT596 is the first off-the-shelf (not the patient’s own gene-modified cells) cellular immunotherapy that is genetically engineered to contain three active antitumor modalities: a proprietary chimeric antigen receptor optimized for NK-cell biology that targets B-cell antigen CD19; a novel high-affinity, non-cleavable CD16 Fc receptor that has been modified to augment antibody-dependent cellular cytotoxicity; and an IL-15 receptor fusion (IL-15RF) that promotes enhanced NK-cell activity. The design of the CAR-NK product enables it to be combined with rituximab with the intent to achieve lasting remission.
FT596 has recently been granted investigational new drug (IND) status by the U.S. Food and Drug Administration (FDA) and is entering clinical trials. A first-in-human phase I trial is planned for early 2020 in patients with B-cell lymphoma and chronic lymphocytic leukemia. If the results of these trials are favorable, this agent could be manufactured in large quantities and may be available on-demand for use in patients with aggressive B-cell hematologic diseases.
Bahram Valamehr, PhD
“Natural killer cells are the first line of defense of the immune system. We have shown that FT596 has comparable ability to kill cancer cells as CAR T-cell therapy and, in combination with rituximab, killed lymphoma cancer cells no longer responding to CAR T-cell therapy in predictive translational models. In addition, we have taken the concept of traditional pharmaceutical drug development and applied it to cellular therapy,” explained senior study author Bahram Valamehr, PhD, Chief Development Officer, Fate Therapeutics, San Diego, the manufacturer of FT596.
FT596 is poised to overcome several inherent challenges with existing CAR T-cell therapies, including the long wait of several weeks for the manufacturing process, the high cost of treatment, limited accessibility, and issues in manufacturing (such as the number of cells successfully engineered and the purity of those cells). “Not every T cell is engineered, and not every engineered T cell is pristine,” Dr. Valamehr explained at a press conference during the 2019 Annual Meeting & Exposition of the American Society of Hematology (ASH).
The Process
FT596 is derived from master engineered human induced pluripotent stem cells, which are a “novel starting cell source,” according to Dr. Valamehr. Master cell banks can be created from these cells and repeatedly differentiated to generate cancer-fighting immune cells, such as natural killer cells and T cells, resulting in homogeneous engineered cell products. “We can knock out genes in a single cell, and repeatedly use clones to create a pure product,” he explained.
KEY POINTS
- FT596 is the third off-the-shelf adoptive cell therapy from Fate Therapeutics and the first off-the-shelf CAR cellular immunotherapy based on pluripotent stem cell lines.
- FT596 contains three antitumor components: hnCD16, anti-CD19 CAR, and IL-15RF.
- In vivo studies have shown antitum aor activity with FT596 in B-cell malignancies as monotherapy and in combination with rituximab.
- First-in-human trials of FT596 will start in the first half of 2020.
“The process is highly scalable, self-renewable, consistent, and cost-effective,” Dr. Valamehr stated. “FT596 is pure for hematopoietic and natural killer cells. Our initial manufacturing campaigns suggest that each dose may be manufactured for as low as $2,500. The drug product is directly infused and is a true off-the-shelf product that can be administered in the outpatient setting,” he continued.
“Preclinical studies thus far suggest that in vivo, FT596 is highly efficacious in controlling tumor, and in combination with rituximab, tumor control is maintained and the risk of antigen escape is mitigated.”
Other Related Products
In addition to FT596, Fate Therapeutics is developing FT576, which is also manufactured from a renewable master cell bank derived from human-induced pluripotent stem cells and designed to attack dual targets in multiple myeloma: B-cell maturation antigen (BMCA) and CD38 tumor-associated antigens. “The unique features of FT576 enable it to be combined with daratumumab and not elicit fratricide, as a patient’s natural killer cells typically express CD38 and are significantly reduced following administration of daratumumab,” Dr. Valamehr explained.
Another product in the pipeline, FT819, is a stand-alone, first-of-kind off-the-shelf CAR T-cell therapy with a knockout T-cell receptor (TCR). “A CAR T-cell therapy that does not express TCR can be used in the allogeneic transplant setting and not induce graft-vs-host disease,” according to Dr. Valamehr. Additional CAR T-cell products are in various stages of development. ■
DISCLOSURE: Dr. Valamehr is employed by Fate Therapeutics, the manufacturer of FT596.
REFERENCE
1. Goodridge JP, Mahmood S, Zhu H, et al: Translation of first-of-kind multi-antigen targeted off-the-shelf CAR-NK cell with engineered persistence for the treatment of B-cell malignancies. 2019 ASH Annual Meeting & Exposition. Abstract 301. Presented December 7, 2019.
